Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/74830
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Type: Journal article
Title: ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression
Author: Ahn, Y.
Gibbons, D.
Chakravarti, D.
Creighton, C.
Rizvi, Z.
Adams, H.
Pertsemlidis, A.
Gregory, P.
Wright, J.
Goodall, G.
Flores, E.
Kurie, J.
Citation: Journal of Clinical Investigation, 2012; 122(9):3170-3183
Publisher: Amer Soc Clinical Investigation Inc
Issue Date: 2012
ISSN: 0021-9738
1558-8238
Statement of
Responsibility: 
Young-Ho Ahn, Don L. Gibbons, Deepavali Chakravarti, Chad J. Creighton, Zain H. Rizvi, Henry P. Adams, Alexander Pertsemlidis, Philip A. Gregory, Josephine A. Wright, Gregory J. Goodall, Elsa R. Flores and Jonathan M. Kurie
Abstract: Metastatic cancer is extremely difficult to treat, and the presence of metastases greatly reduces a cancer patient’s likelihood of long-term survival. The ZEB1 transcriptional repressor promotes metastasis through downregulation of microRNAs (miRs) that are strong inducers of epithelial differentiation and inhibitors of stem cell factors. Given that each miR can target multiple genes with diverse functions, we posited that the prometastatic network controlled by ZEB1 extends beyond these processes. We tested this hypothesis using a mouse model of human lung adenocarcinoma metastasis driven by ZEB1, human lung carcinoma cells, and human breast carcinoma cells. Transcriptional profiling studies revealed that ZEB1 controls the expression of numerous oncogenic and tumor-suppressive miRs, including miR-34a. Ectopic expression of miR-34a decreased tumor cell invasion and metastasis, inhibited the formation of promigratory cytoskeletal structures, suppressed activation of the RHO GTPase family, and regulated a gene expression signature enriched in cytoskeletal functions and predictive of outcome in human lung adenocarcinomas. We identified several miR-34a target genes, including Arhgap1, which encodes a RHO GTPase activating protein that was required for tumor cell invasion. These findings demonstrate that ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression and provide a compelling rationale to develop miR-34a as a therapeutic agent in lung cancer patients.
Keywords: Cells, Cultured
Cell Line, Tumor
Animals
Humans
Mice
Adenocarcinoma
Lung Neoplasms
Doxycycline
rho GTP-Binding Proteins
Luciferases
Transforming Growth Factor beta
Homeodomain Proteins
Tumor Suppressor Proteins
Transcription Factors
MicroRNAs
Oligonucleotide Array Sequence Analysis
Cell Separation
Statistics, Nonparametric
Neoplasm Transplantation
Signal Transduction
Cell Proliferation
Cell Movement
Down-Regulation
Gene Expression Regulation, Neoplastic
Genes, Reporter
Promoter Regions, Genetic
Mice, 129 Strain
Epithelial-Mesenchymal Transition
Actin Cytoskeleton
Transcriptome
Zinc Finger E-box-Binding Homeobox 1
Rights: Copyright © 2012, American Society for Clinical Investigation
DOI: 10.1172/JCI63608
Grant ID: http://purl.org/au-research/grants/nhmrc/1008327
R01 CA157450
P30 CA125123
Appears in Collections:Aurora harvest 4
Medicine publications

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